Clinical Trials

The EARLY TAVR Trial

Cath Lab Digest talks about the EARLY TAVR trial with principal investigator Philippe Généreux, MD, Gagnon Cardiovascular Institute – Morristown Medical Center, Morristown, New Jersey.

Cath Lab Digest talks about the EARLY TAVR trial with principal investigator Philippe Généreux, MD, Gagnon Cardiovascular Institute – Morristown Medical Center, Morristown, New Jersey.

The EARLY TAVR (Evaluation of Transcatheter Aortic Valve Replacement Compared to Surveillance for Patients with Asymptomatic Severe Aortic Stenosis) trial is a prospective, randomized, controlled, multicenter study. Patients will be randomized 1:1 to receive either transcatheter aortic valve replacement (TAVR) with the SAPIEN 3 THV (Edwards Lifesciences) or clinical surveillance. Patients will be stratified by whether or not they are able to perform a treadmill stress test. Patients who have a positive stress test will be followed in a registry to collect data on subsequent treatment and mortality, as applicable.

Can you tell us about the treatment and eventual disease progression of the asymptomatic aortic stenosis patient?

Defining “asymptomatic” for aortic stenosis (AS) or severe AS patients has always been a challenge, because this is a heterogeneous group. Patients do exist that are truly asymptomatic after a medical visit or further testing. In medical  terms and in the cardiology space, to be asymptomatic in severe AS means that no spontaneous symptoms are present. You don’t have shortness of breath while conducting normal activity in your daily life.

You don’t have angina, you don’t have dizziness, you are not lightheaded or syncoptic during activity or spontaneously, and you don’t have extreme fatigue or any decrease in energy level. One of the issues for patients is that many of these symptoms could be associated with normal aging. Many patients believe that they are not symptomatic even if they have severe AS, because they underestimate and underreport symptoms, and they put what they are experiencing under the umbrella of “aging”. That makes our life difficult as physicians when we ask our patients whether they have symptoms or are fatigued. Patients say no, because they believe what they are experiencing is the normal aging process. It may be that the symptoms are so insidious or the installation of symptoms is so chronic or slow, that patients don’t even realize it; they adapt and retreat from more activity gradually, over a long period of time. The role of the EARLY TAVR trial is to try to better define, first, who is truly asymptomatic. The trial will incorporate patients who are claiming to be asymptomatic with severe AS. We will perform a treadmill stress test, if it is safe to do so. The treadmill stress test will offer clear criteria to identify whether a patient is actually symptomatic. To be “asymptomatic” in the EARLY TAVR trial is to be spontaneously asymptomatic as described by the patient, along with objective proof obtained after a treadmill stress test. Asymptomatic patients after a treadmill stress test will be in the EARLY TAVR trial comparing early transcatheter aortic valve replacement (TAVR) versus clinical surveillance or delayed TAVR when symptoms occur. If patients are asymptomatic by questionnaire, but then go on to have a positive stress test, they will be part of the EARLY TAVR registry. The EARLY TAVR trial will include 1109 patients and the EARLY TAVR registry will include up to 1000 patients. The trial will take place at up to 65 centers in the United States and 10 additional centers outside of the U.S., and the hope is to finalize enrollment within two years.

Do asymptomatic AS patients typically undergo a treadmill stress test or is this something specific to the trial?

That’s a good question. The current American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend the use of a treadmill stress test as a class IIA to decipher between symptoms or no symptoms. But this test is not broadly done throughout the cardiology or internal medicine community. Doctors are nervous to put a patient on the treadmill stress test with high velocity. They worry about an adverse event. One survey from Europe showed only 5-10% of physicians seeing asymptomatic AS patients are using a treadmill stress test. However, it holds a class IIA indication. 

Asymptomatic AS patients are typically monitored by a cardiologist and put on medical therapy?

Exactly, although there is no medical therapy, because these patients are asymptomatic and there are no medications to prevent AS progression. Typically, if a doctor decides to follow a patient, the guidelines recommend a clinical follow-up with an echocardiogram every 6 to 12 months. So the doctor will follow the patient every 6 to 12 months, informing the patient to slow down their activity, not to push themselves too much, and to come back or advise if any symptoms occur. The evolution of severe asymptomatic AS to severe AS with symptoms is very unpredictable and variable. Sometimes it could be a long-lasting period; sometimes it could be very dramatic, unpredictable, and acute. We have had some patients, for example, who were asymptomatic with severe AS, and all of a sudden, they had pneumonia. They became hypotensive and septic, and it spiraled down. At this point, they are in trouble. Some doctors will follow the asymptomatic AS patient more closely, perhaps every 3 months with a treadmill stress test. There is a spectrum, with some physicians following patients every year versus every 3 months, and the problem is that even if you follow these patients carefully, it is still very difficult to predict when the patient will become symptomatic. When the patient does become symptomatic, the mortality for severe AS increases to 20-30% per year, compared to a range of between 1-5% per year mortality when there are no symptoms. That is the reason we are focusing so much on when a patient is symptomatic. But this conversion of no symptoms to symptoms is very difficult to identify and variable for each patient.

What happens to the heart in these asymptomatic patients?

There are three class I indications to intervene in severe AS with no symptoms: One is ejection fraction less than 50%, second would be need for concomitant valve or coronary surgery, and third is induced symptoms on a low-level treadmill stress test. If a patient has severe AS, no symptoms, and a normal EF, the first cardiac compensation will be that the LV gets very thick, because in order to compensate for this obstruction, the heart works very hard to push the blood through the aortic valve, which is narrow, so it becomes very stiff and there is some diastolic dysfunction. The capacity to receive blood is reduced by the heart. Second, it is possible to have dilation of the left atrium, progression to atrial fibrillation, and an increase in lung pressure. All this can be done insidiously, with some cardiac damage occurring without symptoms. When the symptoms become obvious, then we replace the valve, but the damage stays forever, despite the valve being replaced. This is the basis of the EARLY TAVR trial, to identify whether early intervention before symptoms will prevent not only mortality, but will prevent the installation of irreversible damage such as LV dysfunction, LV dilation, atrial fibrillation, and so on. 

Have previous trials brought us to this point?

Yes. The TAVR journey started with the sickest of the sickest patients; those with severe AS with symptoms being deemed inoperable, or at high risk or extreme risk for surgical AVR, then moved to intermediate risk patients, and recently to low risk patients. But all of the previous studies involved patients with symptoms. The EARLY TAVR trial is an all-comers trial including patients with no symptoms and an Society of Thoracic Surgeons (STS) score lower or equal to 10%. 

How far out is the EARLY TAVR trial following patients?

The primary endpoint is 2 years, but we are going to follow patients out to 5 years. 

Could you talk more about inclusion criteria? 

The EARLY TAVR trial will include only patients 65 years old and above. Patients need to have a tricuspid valve; bicuspid valves are excluded. After a very thorough and deep questionnaire, patients must have indicated they are asymptomatic. If they are capable of walking and we feel it is safe to do a treadmill test, they will do so. If patients are not capable of a treadmill test, the EARLY TAVR trial allows for 30% of patients to be randomized without a treadmill test, pending a compelling reason not to do so, meaning an orthopedic issue, knee issue, etc. With the treadmill test, which will include the vast majority of patients, there are four criteria we use for a positive test. The first criteria would be a spontaneous symptom on the treadmill at any time, including chest pain, syncope, and dizziness. Second is the presence of ventricular arrhythmia (defined as four or more consecutive ventricular ectopic beats). Third, a sustained drop in blood pressure equal to or greater than 20 mmHg. Fourth is test-limiting dyspnea or fatigue below 60% of their METs capacity adjusted for age and sex.

Does the trial require standardization of any particular aspect of TAVR?

Yes. Similar to previous trials, the EARLY TAVR trial is mandating that the TAVR be performed by a heart team with both an interventional cardiologist and a surgeon in the room. It should take place in a hybrid room or in a cath lab with the capacity to convert to an open-heart surgery if needed. An anesthesiologist must also be in the room. At Morristown, we prefer to do everyone under general anesthesia, because it gives us the luxury of a safety net. However, if an investigator wanted to do conscious sedation, they are allowed, but need to be extremely comfortable in doing so. 

Do you expect an age cluster at all?

The previous PARTNER trials included patients around 80 years old. The EARLY TAVR trial might trend a little bit younger, but still will include patients in their 70s. We are excluding bicuspids and patients below 65 years old. Further study probably will be performed with younger ages and with bicuspids in the near future.

Are you anticipating mostly femoral access?

The EARLY TAVR trial will enroll only patients suitable for femoral access. If femoral access cannot be utilized safely, those patients will be excluded.

What about the use of embolic protection?

There is no clear evidence with the Sapien 3 valve that the use of an embolic protection device will result in a lower risk of clinical stroke or clinically significant neurological event. So regarding the EARLY TAVR trial, an embolic protection device is not mandated at all; however, if a center wants to use an embolic protection device, they will be allowed to do so.

Are there any aspects of the Sapien 3 valve that may be particularly useful for treating patients?

We are targeting, for the first time, a lower-risk and asymptomatic population. 

The Sapien 3 valve has demonstrated one of the best safety profiles in terms of stroke, vascular complications, and paravalvular leak. More importantly, the Sapien 3 valve offers a very reproducible and predictable result with ease of use for all operators.

Can you share some of the history of TAVR at your facility?

The TAVR program at Morristown Medical Center started in 2010 and we are on track to do approximately 450 TAVRs this year. We are the largest program in the state of New Jersey. We have a very good collaboration between our cardiothoracic surgeons and cardiologists, and we have had good outcomes so far. I do think it is because we collaborate so well together. Morristown Medical Center enrolled the first patient in the EARLY TAVR trial on July 12th.

What do you anticipate if the EARLY TAVR trial shows a positive benefit for asymptomatic AS patients? 

This trial has the potential to be a paradigm shift in the way we not only treat, but also follow, patients with severe AS with no symptoms. It has the potential to change the guidelines in terms of the way we approach and manage AS patients with no symptoms. There is a very high proportion of patients that claim to be asymptomatic, but in fact are symptomatic. So far, no prospective large series or randomized trial has been performed. The EARLY TAVR trial will, for the first time, study this patient population. Severe AS with no symptoms is a very common problem encountered by general cardiologists. The EARLY TAVR trial has the potential to educate clinicians managing these patients, and potentially provide a definitive answer to how to manage these patients. 

Disclosures: Dr. Philippe Généreux reports that within the past 12 months, he has consulted and received speaker fees from both Edwards Lifesciences and Medtronic; he has also been a proctor and received a research grant from Edwards Lifesciences.

Dr. Philippe Généreux can be contacted at philippe.genereux@atlantichealth.org.